Investigation of the role of the nuclear receptor NR4a1 during bone turnover and maintenance of the hematopoietic niche in the bone marrow

代谢和炎症性疾病都伴有骨质疏松症的加重，其特点是骨形成和骨吸收之间的平衡发生了变化。破骨细胞介导骨吸收增加的过程，是骨质疏松发病的关键细胞。核受体是脂肪和葡萄糖代谢的中枢调节因子。此外，它们还参与了炎症反应的调节。我们小组的初步数据显示核受体NR4A1在单核细胞谱系中高表达，包括巨噬细胞和破骨细胞。此外，这些数据表明该转录因子具有骨代谢和炎症调节的双重作用。本项目旨在进一步阐明NR4A1在体内外骨代谢和炎症中的作用。我们将研究NR4A -/-小鼠，应用绝经后骨质疏松症（卵巢切除模型）、炎症性骨质疏松症（TNFα-转基因小鼠）和关节炎小鼠模型（TNFα-转基因小鼠模型和K/BxN血清转移）的实验模型。利用分子方法，我们将寻求鉴定NR4A蛋白家族的靶基因，并表征其在巨噬细胞、破骨细胞和成骨细胞等关键细胞中的功能。这些实验将有助于了解核受体NR4A家族在慢性炎症性疾病（如类风湿关节炎（RA））和骨代谢相关变化中的作用，从而最终确定治疗这些疾病的新靶点。

Both metabolic and inflammatory disorders are accompanied by aggravated osteoporosis, which is characterized by a shifted balance between bone formation and bone resorption. Osteoclasts are key cellular players in the pathogenesis of osteoporosis since they mediate the process of increased bone resorption. Nuclear receptors are central regulators of fat and glucose metabolism. Moreover, they have been implicated in the modulation of the inflammatory response. Preliminary data of our groups show high expression of the nuclear receptor NR4A1 in cells of the monocytic lineage including macrophages and osteoclasts. Moreover these data indicate a dual role of this transcription factor both as regulator of bone metabolism and of inflammation. It is the aim of this project to further elucidate the role of NR4A1 in bone metabolism and inflammation in vivo and in vitro. We will study NR4A -/- mice and apply experimental models of postmenopausal osteoporosis (ovariectomy model), inflammatory osteoporosis (TNFα-transgenic mice) and mouse models of arthritis (TNFα- transgenic mouse model and K/BxN serum transfer). Using molecular approaches we will seek to identify target genes of the NR4A family of proteins and characterize their function in key cells such as macrophages, osteoclasts and osteoblasts. These experiments will help to understand the role of the NR4A family of nuclear receptors during chronic inflammatory disorders such as rheumatoid arthritis (RA) and during associated changes in bone metabolism, which will eventually lead to the identification of novel therapeutic targets for the treatment of these diseases.